Essential hypertension (EHYT) is a common chronic disease contributing to morbidity, morality, and cost of health care. This renewal application is a continuation of our work to understand the genetic basis of interindividual variation in risk of EHYT in the population at large using the Rochester Family Heart Study (RFHS). This resource involves 4053 members of 560 multigeneration pedigrees ascertained without regard to health status who have undergone a physical examination and provided blood for laboratory studies. This resource is being utilized to address three major questions: 1) Which intermediate biochemical, physiological, and anthropomorphic traits predict blood pressure (BP) and contribute to the pathogenesis of EHYT? 2) Does allelic variation in one or more genes have large effects on any of these intermediate traits? 3) Does information about allelic variation improve prediction of risk of EHYT beyond what is provided by measure of the intermediate traits? AIMS 1-4 of this application focus on the first question, AIM 5 on the second, and AIM 6 on the third. AIM 1 will use 120 RFHS pedigrees to determine whether the single genetic or environmental factor identified as having a large effect on erythrocyte (RBC) sodium-lithium countertransport (NA-Li CNT) has a large impact on RBC and/or lymphocyte sodium-hydrogen exchange activity. AIM 2 seeks to determine whether measures of renal hemodynamic non- modulation (on high salt diet), renal tubular sodium (Na+) reabsorption, insulin resistance, heightened sympathetic nervous system activity, or alterations in lipid metabolism explain the statistical association between elevated Na-Li CNT and development of EHYT in these pedigrees. AIM 3 will establish the extent to which measures of the 24-hour ambulatory BP profile can be explained by traits studied in AIM 1 and 2. AIM 4 will consider 800 unrelated members of 294 RFHS pedigrees to determine if RBC Na-K ATPase pump, sodium-potassium cotransport, intracellular Na+, or plasma levels of atrial natriuretic peptide contribute to prediction of EHYT. AIM 5 will use all 2049 participants of these pedigrees to establish whether one or more single genes have major effects on traits identified as predictors of EHYT in AIM 4. AIM 6 will estimate the relative contribution of genes identified in AIM 5 to the prediction of EHYT.